Systemic Onset Juvenile Chronic Arthritis (SOJCA) is a disease that carries severe long-term disability for 50% of the children who suffer from it. The pathogenesis of this disease remains a mystery and there are no animal models to reproduce it. As opposed to other forms of Juvenile Chronic Arthritis, no serologic markers like autoantibodies, HLA associations, or other specific diagnostic tests are available. We now have preliminary data showing significant alterations in the blood mononuclear cells from SOJCA patients, including 1) increased numbers of blood monocytes with an activated phenotype, 2) a gene signature shared with patients with bacterial infections, 3) a unique gene signature. The present proposal aims at further strengthening these data through the accrual of a larger number of patients and the analyses of a larger selection of genes. We expect that these studies will provide us with clues to understand the pathogenesis of the disease. We are particularly intrigued by the similarities observed between SOJCA and systemic infections especially with those caused by Staphylococcus aureus. We propose to correlate the SOJCA genetic signature with the outcome of the disease. In particular, the four-year proposed study will permit us to compare the gene profiles of patients who get disease resolution from those who develop a chronic, highly debilitating disease. In vitro studies are designed to eventually identify the cellular and molecular mechanisms leading to the SOJCA signature, thereby allowing us to better understand the disease. Our ultimate goal is to design novel therapies to antagonize the causative agent and/or the genetic pathways responsible for the establishment of this intriguing disease.